title: A chemically modified antibody mediates complete eradication of tumours by selective disruption of tumour blood vessels.
abstract: BACKGROUND
  The possibility of eradicating cancer by selective destruction of tumour blood vessels may represent an attractive therapeutic avenue, but most pharmaceutical agents investigated so far did not achieve complete cures and are not completely specific. Antibody conjugates now allow us to evaluate the impact of selective vascular shutdown on tumour viability and to study mechanisms of action.
  
  
  METHODS
  We synthesised a novel porphyrin-based photosensitiser suitable for conjugation to antibodies and assessed anticancer properties of its conjugate with L19, a clinical-stage human monoclonal antibody specific to the alternatively spliced EDB domain of fibronectin, a marker of tumour angiogenesis.
  
  
  RESULTS
  Here we show in two mouse model of cancer (F9 and A431) that L19 is capable of highly selective in vivo localisation around tumour blood vessels and that its conjugate with a photosensitiser allows selective disruption of tumour vasculature upon irradiation, leading to complete and long-lasting cancer eradication. Furthermore, depletion experiments revealed that natural killer cells are essential for the induction of long-lasting complete responses.
  
  
  CONCLUSIONS
  These results reinforce the concept that vascular shutdown can induce a curative avalanche of tumour cell death. Immuno-photodynamic therapy may be particularly indicated for squamous cell carcinoma of the skin, which we show to be strongly positive for markers of angiogenesis.
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zürich, Wolfgang-Pauli-Strasse 10, Zürich 8093, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Palumbo
authors.forename: F
authors.initials: F
authors.lastname: Hauler
authors.forename: P
authors.initials: P
authors.lastname: Dziunycz
authors.forename: K
authors.initials: K
authors.lastname: Schwager
authors.forename: A
authors.initials: A
authors.lastname: Soltermann
authors.forename: F
authors.initials: F
authors.lastname: Pretto
authors.forename: C
authors.initials: C
authors.lastname: Alonso
authors.forename: G F
authors.initials: GF
authors.lastname: Hofbauer
authors.forename: R W
authors.initials: RW
authors.lastname: Boyle
authors.forename: D
authors.initials: D
authors.lastname: Neri
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D005455:Fluorescent Antibody Technique; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010778:Photochemotherapy
chemical_list: D018796:Immunoconjugates